It is estimated that one seventh of the US population suffer from some forms of musculoskeletal impairment. The social and economic implications of the effective treatment of these conditions are enormous. The goal of this project is to design osteoconductive and osteoinductive synthetic bone grafts possessing desirable mechanical strength and biochemical microenvironment for the reconstruction of skeletal defects with compromised natural healing capacities. The grafts are designed to provide instant mechanical protection and structural stabilization to the site of bony defects, and locally release exogenous growth factors and cytokines to promote bone graft healing. Specifically, we propose to incorporate an exogenous supply of BMP-2, RANKL and VEGF to the synthetic bone graft to induce proper host cell responses to elicit the coordinated remodeling and osteointegration of the graft with vascular ingrowth. Using ring opening polymerization and reverse addition fragmentation transfer polymerization in combination with high-fidelity bioconjugation chemistries, polymeric biodegradation domains, growth factor retention domains, bone mineral (hydroxyapatite) nucleation domains and cell adhesion domains are sequentially grafted around Si-based nanoparticle cores. The resulting injectable star-shaped macromers are then crosslinked in the absence or the presence of calcium apatite to generate bulk polymer or polymer-mineral composite bone grafts. The modular design enables that each functional domain of the graft be independently modulated to optimize the overall performance of the graft. A detailed strategy is proposed to characterize the structural and mechanical properties, the degradation characteristics, the HA-nucleation capacity and the bioactivities of the synthetic bone graft in vitro. In addition, a rat femoral segmental defect model that takes into account the weight-bearing nature of the musculoskeletal tissue is utilized to evaluate the in vivo performance and viability of the synthetic graft. The extent and quality of the remodeling, vascularization and osteointegration of the graft as a function of polymer domain compositions, osteoconductive mineral contents and the exogenous signaling molecules locally released from the grafts will be analyzed by histology, microcomputed tomography, electron microscopy and torsion tests.